Despite considerable research efforts, cancer remains one of the major causes of death throughout the world (R. Siegel et al.: Cancer Statistics 2012, 2012, 62, 10-29). Among the various types of cancer, lung cancer constitutes the principal cause of cancer-associated death (J. S. Guthi et al., Molecular Pharmaceutics, 2009, 7, 32-40):                there are 1.4 million deaths throughout the world each year,        the 5-year survival rate is less than 15%.        
The low survival of patients suffering from lung cancer is mainly due to the absence of tools for early diagnosis and for locally targeting therapeutic agents.
The use of nanoparticles as a contrast agent in medical imaging or as a therapeutic agent has been known for more than two decades. These nanoparticles in fact have many advantages compared with molecular compounds:
they allow a multimodal approach (M. Lewin et al., Nat. Biotechnol., 2000, 18, 410-414),
                detection is much improved owing to the greater number of active elements per particle; furthermore, in the case of MRI, the efficiency per Gd3+ ion is also improved (P. Caravan, Chem. Soc. Rev., 2006, 35, 512-523/J. S. Ananta et al., Nat. Nano., 2010, 5, 815-821),        it is possible to graft several molecules of a particular ligand per nanoparticle and/or to combine several types of ligands per nanoparticle in order to increase the affinity of the nanoparticles for certain tissues or cell types depending on the application envisioned (E. Garanger et al., Org. Biomol. Chem., 2006, 4, 1958-1964/Z.-H. Jin et al., Molecular Cancer, 2007, 6, 41),        their nanometric scale confers on them novel and original properties that can be used for biomedical applications (E. Boisselier, D. Astruc, Chem. Soc. Rev., 2009, 38, 1759-1782/C. Xu, S. Sun, Dalton Trans., 2009, 5583-5591/P. Zrazheveskiy et al., Chem. Soc. Rev., 2010, 39, 4326-4354),        they are rigid, and exhibit little interaction with the biological medium.        
The multimodal approach consists in particular in using a set of nanoparticles each comprising several molecular contest agents. It thus makes it possible to combine not only various imaging techniques, but also various therapeutic techniques by grouping together several agents that are active in therapy, in the same nanoparticle. The agents that are active in imaging and the agents that are active in therapy can be identical to or different than one another.
This approach is particularly suitable for the development of medicament in theranostics. It is also possible in particular to add other imaging functions (luminescence, scintigraphy, etc.), therapeutic functions (release of active ingredients, radiosensitization, curietherapy, etc.) and also biological targeting functions for concentration of therapeutic agents in the zone of interest. This approach makes it possible in particular to envision imaging-guided therapy by accurately determining the behavior of the theranostic agent in the body by virtue of its biodistribution visualized by imaging. The theranositc agent can then be activated (by X-rays, γ-rays, neutrons or light, according to the type of agent) at the best moment (when the concentration is at a maximum in the zone to be treated and at a minimum in the healthy tissues).
Patent application WO 2009/053644 describes nanoparticles based on lanthanides (gadolinium in particular) and uses thereof as radiosensitizing agents. It discloses the use of organic molecules at the surface or in the coating of nanoparticles, so as in particular to improve biodistribution and to promote local overconcentrations in the tumor zones.
Patent application WO 2011/135102 describes ultrafine nanoparticles, with a mean diameter of less than 5 nm, comprising a functionalized polyorganosiloxane matrix and including metal complexes, for example of gadolinium, and where appropriate other contrast or radiosensitizing agents. These ultrafine nanoparticles have multimodal properties which are particularly advantageous in medical imaging and in cancer therapy. After an intravenous injection, an excellent biodistribution is noted along with rapid and complete renal elimination owing to their very small size, thereby limiting the risks of side effects or toxic effects (F. Lux et al., Ange. Chem. Int. Ed., 2011, 123, 12507-12511).
The lung is a unique organ in the sense that it can be targeted by a diagnostic or therapeutic agent either intravenously or via the airways. However, the administration of nanoparticles that can be used as a contrast agent is conventionally carried out by intravenous injection owing to the risks of long-term retention in the lungs (and therefore of associated tonicity) (J. Roller et al., Nanomedicine, 2011, 7, 753-762/R. Rossin et al., J. Nucl. Med., 2008, 49, 103-111).
In CT (computed tomography), the administration by inhalation of nanoparticles based on heavy elements (for example, gold (Cai, S. H. et al, Investigative Radiology, 2007, 42, 797-806) and iodinated compounds (Aillon, et al, Molecular Pharmaceutics, 2010, 7, 1274-1282)) has been described. In magnetic resonance imaging (MRI), only negative contrast agents (iron oxide-based nanoparticles (G. Huang et. al., Chem., 2009, 19, 6367-6372)) have been used via the airways because of their low toxicity and the ease with which they can be synthesized and functionalized. However, the use of a negative contrast agent is not optimal for imaging the lung, and the diagnosis might be improved by using positive contrast agents.
For fluorescence imaging, near-infrared (NIR) emission nanoparticles, such as quantum dots, have been used, but their inherent toxicity limits the possible future clinical applications. A. Zintcheko et al., Molecular Therapy, 2009, 17, 1849-1856/F-X. Blé et al, Magnetic Romance in Medicine 62:1164-1174 2009 describe the synthesis and the in vivo behavior of molecules capable of labeling mucus in order to study mucociliary clearance mechanisms. They show the advantage of using a fluorophore in the near-IR and also a contrast agent T1 for their macromolecules. This approach does not make it possible to obtain a strong MRI signal (4 Gd3+ for molecules of more than 10 kDa) or else it is necessary to dextran polymers of much higher molar mass (greater than 70 kDa). Furthermore, these polysaccharide-type polymers are biologically active and can interact with the glycoproteins of the mucus to bind to sites rich in hydrogen bonds. The contrast agent is eliminated by expectoration and does not make it possible to obtain an enhancement of the pulmonary tissues.
Thus, to the knowledge of the inventors, via administration, via the airways, of gadolinium-based nanoparticulate multimodal contrast agents has never been described for T1 MRI imaging of the lungs. The inventors have now shown that an administration, via the airways, of a contrast agent in the form of ultrafine nanoparticles (with a mean diameter of less than 10 nm, or even less than 5 nm, for example between 1 and 5 nm) allows a contrast agent distribution that is particularly favorable for imaging of the lung or therapy for pathological pulmonary conditions and a satisfactory renal elimination, thus limiting the risks of toxicity that are inherent in structures of this type.